2.3. Polihexanide

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to amend the current entry for polihexanide in Schedule 6 in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are as:

The applicant’s reasons for the request are:

• Polihexanide is a polymer of chlorhexidine (listed in Schedules 5 and 6 of the Poisons Standard).
• Polihexanide has reported cosmetic and domestic uses overseas, as preservative and biocide, in products that are potentially available for use in Australia;
• Polihexanide has moderate acute oral and inhalation toxicity, are highly irritating to the eyes, are moderate skin sensitisers, and present a moderate hazard from repeated inhalation toxicity; and
• Overseas restrictions exist for the use of polihexanide in cosmetic products where the maximum concentration allowed is 0.3%.
• The 2015 Scientific Committee on Consumer Safety (SCCS) Opinion of poly(hexamethylene)biguanide hydrochloride (PHMB) or polihexanide. The Opinion indicated that the chemical is not considered safe as a preservative in all cosmetic products at up to 0.3%.
• The SCCS released the 2017 Opinion of PHMB. The opinion indicated that the safe level of use of polihexanide as a preservative in cosmetic products is 0.1%. As a result of this Opinion, a restriction process in the EU to lower the cut-off is expected in the short- to medium-term. The Cosmetic Ingredient Review (CIR) Expert Panel 2017 safety assessment of polihexanide (currently for public comment) as used in cosmetics. The IMAP Human Health Tier II assessment will be re-published in November 2017 to include these two recent reports.
• While the re-published assessment may recommend further restriction of cosmetic and domestic use concentrations, referral for Scheduling for any further restrictions will need to consider finalisation of any further EU restrictions. This may take some time, and the current absence of a specific restriction on use of polihexanide in cosmetic and domestic products in Australia poses a risk to public health.

Current scheduling status

Polihexanide is currently listed in Schedule 6 and in Appendices E and F of the Poisons Standard as follows:

Chlorhexidine (polihexanide is a polymer of chlorhexidine) is in Schedules 7, 6 and 5 of the Poisons Standard as follows:

Scheduling history

May 1977 Poisons Schedule (Standing) Committee (PSC)

In May 1977, the Poisons Schedule (Standing) Committee (PSC) considered the substance (at that time it was called poly(hexamethylene biguanide) hydrochloride) and decided to list it in Schedule 5 and the then Appendix A (now Appendix E). The reason for these entries was its LD₅₀ in the rat was 1 g/kg (toxicity end-point details were not provided).

November 1982 Poisons Schedule (Standing) Committee (PSC)

In November 1982, the PSC considered an application requesting that preparations containing less than 20% of poly(hexamethylene biguanide) be exempted from scheduling. The PSC did not accept the proposal because of concerns over "equivocal" results in developmental studies in rats, low survival rate in sub-acute oral studies in rats, and severe eye irritancy. The PSC, however, agreed to a 5% cut-off as exempt from scheduling, on the basis that poly(hexamethylene biguanide) was not a skin or eye irritant at that concentration.

November 2000 National Drugs and Poisons Schedule Committee (NDPSC)

In November 2000, the NDPSC decided to change the nomenclature of the Schedule 5 entry from poly (hexamethylene biguanide) hydrochloride to polihexanide. This decision was to reflect the World Health Organisation's decision to use the International Non-proprietary Name (INN).

November 2014, Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS#10)

In June 2011, the Australian Pesticides and Veterinary Medicines Authority's (APVMA) released an updated report, 'polihexanide carcinogenicity: analysis of human health risk', based on an OCS evaluation on the carcinogenicity potential of polihexanide. The report indicated that polihexanide has a potential for carcinogenicity in whole-of life studies in rodents via the oral route, but only at high exposure levels that are unlikely to be encountered in occupational or public settings. Negative results were obtained in an 80-week dermal study in mice. There were no carcinogenic effects on skin. The occurrence of haemangiosarcoma in the liver at the high dose in the dermal study was considered not to be treatment related as it was within historical controls. Polihexanide did not appear to be genotoxic. The OCS evaluation report did not regard carcinogenicity findings in rodents as a barrier to continuing registration of products containing polihexanide.

 

In September 2014, the Office of Chemical Safety (OCS), based on the APVMA's review on polihexanide, submitted a proposal to delete the current Schedule 5 polihexanide entry and create a new Schedule 6 entry for preparations containing more than 5% of polihexanide. This application was considered at the November 2014 Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS#10). The committee recommended that the current Schedule 5 polihexanide entry be deleted and a new Schedule 6 entry be created for preparations containing more than 5% of polihexanide. The committee also recommended that the new entry specifically exempt from scheduling preparations containing polihexanide when packed and labelled for therapeutic use; and that a First Aid Statement 'E1 - If in eyes wash out immediately with water' be applied. The delegate agreed based on the critical toxicological endpoints driving this categorisation (acute toxicity, severe skin/eye irritancy and sensitisation potential) consistent with SPF criteria for listing in Schedule 6, and given the public health risk sufficiently ameliorated for products under 5 per cent. This was implemented on 1 June 2015.

Australian regulatory information

The applicant states that no restrictions in Australia exist for using polihexanide in cosmetic or domestic products.

Polihexanide (as polyhexamethlenebiguanidine) is an ingredient in 8 products on the ARTG including contact lens solution, irrigation fluid for medical/surgical procedures, dental material for root fillings, sanitising wipes and disinfectant spray.

According to the ARTG database, Polyhexamethlenebiguanidine (PHMB) is permitted for use as an excipient in Devices only. It is not currently used in any PI formulations.

There are no recorded adverse events in the Database of Adverse Event Notifications – media devices for polyhexamethlenebiguanidine.

Polihexanide is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017. However, the similar compound polyaminipropyl biguanide (CAS No. 133029-32-0, Figure 1 below) and chlorhexidine (as the acetate and gluconate) are listed as follows:

List of chlorhexidine (as the acetate and gluconate)

	Ingredient Name	Purpose of the ingredient in the medicine	Specific requirements
3908	POLYAMINOPROPYL BIGUANIDE	E	Only for use in topical medicines for dermal application and not to be included in medicines intended for use in the eye. The concentration in the medicine must be no more than 0.3%.
1298	CHLORHEXIDINE ACETATE	E	Only for use in topical medicines for dermal application.
1299	CHLORHEXIDINE GLUCONATE	E	Only for use in topical medicines for dermal application.

International regulations

The chemicals are permitted as preservatives in cosmetic products in the EU and NZ at a maximum permitted concentration of 0.3%.

The use of polihexanide in cosmetics in the European Union (EU) is subject to the EU Cosmetics Regulation 1223/2009 Annex V—List of preservatives allowed in cosmetic products. Polihexanide may be used as preservatives in cosmetic products at a maximum permitted concentration of 0.3%. According to the 2017 SCCS opinion a reduction in this concentration was recommended, but this has not yet been finalised, nor implemented in legislation.

Polihexanide are also listed, with similar use restrictions described above, in the NZ Cosmetic Products Group Standard—Schedule 7.

Substance summary

Table 2.3.1: Chemical properties for polihexanide

Property	Polihexanide
CAS numbers	32289-58-0 27083-27-8 28757-47-3 133029-32-0
Chemical structure
IUPAC, CAS and/or common and/or other names	Poly(iminocarbonimidoyliminocarbonimidoylimino-1,6-hexanediyl); polyhexamethylene biguanide (PHMB); 1-(diaminomethylidene)-2-hexylguanidine (IUPAC); Polyaminopropyl Biguanide (INCI)

Polihexanide (polyhexamethylene biguanide hydrochloride or PHMB) is a polymer of chlorhexidine and a preservative ingredient/biocide in cosmetics and domestic products and therapeutic goods including disinfectants and sanitisers.

Polihexanide is used as an active ingredient in various preparations such as wet wipes, wound irrigation solutions, sterile dressings as well as disinfectants (e.g. medical equipment, medical procedures, contact lens cleaners, food preparation surfaces, industrial situations, veterinary products and milk handling equipment). Polihexanide is also used an antimicrobial for the control of microorganisms, algae and fungi in swimming pools and spas.

Due to its excellent biocidal properties, the usage of polihexanide has increased in personal care products and pharmaceuticals, for instance in the treatment of chronic wounds and burns. This widely used biocide has been reviewed by the US EPA, which noted that the biocide has very low aggregate risk of adverse health effects to the public or environment, except for occupational users.

Polihexanide binds to the negatively charged phosphate head groups of phospholipids on the bacterial cell wall causing increased rigidity by sinking nonpolar segments into hydrophobic domains, and membrane disruption with subsequent cytoplasmic shedding, culminating in cell death. The antibacterial activity of polihexanide depends on its molecular structure. Minimum requirements for biocidal activity are met by having more than 2 biguanide moieties and 5-7 methylene groups as a spacer. Therefore, polihexanide represents an oligomeric substance with a number-average degree of polymerization of 2-5. It is a cationic biocide marketed worldwide, because of its excellent antimicrobial activity, chemical stability, low toxicity and reasonable cost. Polihexanide is highly soluble in water (20%, w/v) and aliphatic alcohols, but poorly soluble in nonpolar liquids. The biguanide moieties are strong bases and monoprotonated at a pH value of 7 (pKa1=2–3; pKa2=10.5–11.5) resulting in a polycation with a positive charge at each biguanide moiety^[55]

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for polihexanide.

Table 2.3.2: Acute toxicity end-points for polihexanide

Toxicity	Species	Polihexanide	SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw)	Rat	501-1049 mg/kg bw	Schedule 6
Acute dermal toxicity LD50 (mg/kg bw)	Rat, Rabbit	>2000 mg/kg bw	Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h)	Rat	0.29-0.48 mg/L/4 hours (290-480 mg/m3/4 hours)	Schedule 7
Skin irritation	Rabbit	Slightly irritating	Schedule 5
Eye irritation	Rabbit	Highly irritating	Schedule 6
Skin sensitisation (GPMT, Buehler)	Guinea pig	Moderate	Schedule 6

Polihexanide has moderate acute toxicity based on results from animal tests following oral exposure, with median lethal dose (LD₅₀) values ranging from 501-1049 mg/kg bw. Observed sub-lethal effects in these studies included lethargy, ataxia, salivation, laboured breathing, lacrimation, piloerection, and partial drooping of the upper eyelids (ptosis).

Polihexanide has low acute toxicity based on results from animal tests following dermal exposure, with LD₅₀ values > 2000 mg/kg bw.

Polihexanide has high acute toxicity based on results from animal tests following inhalation exposure, with median lethal concentration (LC₅₀) values ranging from 0.29-0.48 mg/L/4 hours. Observed sub-lethal effects in these studies included breathing irregularities, abnormal respiratory noise, partial drooping of the upper eyelids (ptosis), decreased activity and pathological changes in the lungs.

Irritation

Polihexanide, when applied at neat concentrations, is slightly irritating to rabbit skin.

Polihexanide is highly irritating to rabbit eyes

In a study compliant with the Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 405, 0.1 mL of neat polihexanide was instilled into the conjunctival sac of one eye of a male New Zealand White (NZW) rabbit. The other eye was used as a control. The treatment-related effects on the cornea, iris, and conjunctivae were evaluated at the following time points: 1, 24, 48, 72 hours; and 7, 14, 21 days. This single treatment resulted in corneal opacity (opalescent), iridial inflammation and severe conjunctival irritation. Additionally, other treatment-related effects observed include vascularisation and pale appearance of the nictating membrane. These changes were not reversible by 21 days. Considering the severity of the effects, no additional animals were used in the study. Although there were no irritation scores provided, polihexanide was considered corrosive to the rabbit eye following this single application.

Similar results to the study above were reported in another neat application of the chemical to NZW rabbits.

Sensitisation

Based on the available information from guideline-compliant studies in animals, polihexanide is considered to be a moderate skin sensitiser.

In an OECD TG 406-compliant guinea pig maximisation study in Alpk:Dunkin Hartley guinea pigs, intradermal induction used 0.06% polihexanide under occlusive conditions for 48 hours. Topical induction was with 20.2% polihexanide solution. The challenge concentrations used were 20.2% and 6% polihexanide under occlusive condition for 24 hours. The ensuing skin reactions were observed and scored 24 or 48 hours following patch removal. In the guinea pigs challenged with 20.2% polihexanide, scattered redness or moderate diffuse redness were observed in 18/20 and 16/20 animals 24 and 48 hours after patch removal, respectively. The average scores for redness were 1.4 at 24 hours and 1.2 at 48 hours. Similar effects were observed in some animals challenged with 6% polihexanide: 5/20 after 24 hours; and 2/20 48 hours after patch removal. The average scores were 0.3 at 24 hours and 0.1 at 48 hours. Under these tests conditions, polihexanide is considered to be a moderate sensitiser. However, the SCCS has noted that, at 20.2%, polihexanide 'should be considered a strong sensitiser according to Regulation (EC) No 1272/2008 (CLP regulation)'.

Results from several other guinea pig maximisation tests and Buehler studies conducted according or comparable to OECD 406 support the observations of the critical study above.

Repeat-dose toxicity

Based on the available information from guideline-compliant studies in animals, polihexanide is not expected to cause serious damage to health following repeated oral or dermal exposure.

Based on the treatment-related effects reported in repeated dose toxicity studies, repeated inhalation exposure to polihexanide is considered to cause serious damage to health.

In a 28-day repeated dose inhalation toxicity study in male and female Wistar-derived [Alpk:APfSD] rats, the no observed adverse effect concentration (NOAEC) for polihexanide was reported to be 0.0239 mg/m³ (nominal concentration). In this OECD TG 412-compliant study, rats were exposed nose-only to 0.025, 0.25, and 2.5 mg/m³ polihexanide for 6 hours a day, 5 days a week for 28 days. Measured concentrations were 0.0239 mg/m³ (particle size range - 0.32-1.30 μm); 0.257 mg/m³ (particle size range - 0.48-5.06 μm); and 2.47 mg/m³ (particle size range - 0.67-1.67 μm). The recovery period following treatment was 13 weeks. Changes in bodyweight and food consumption were observed in males exposed to 0.25 or 2.5 mg/m³ polihexanide. No deaths occurred in any of the treatment groups. Histopathological analysis showed transient changes in the larynx and trachea in animals from the 0.25 and 2.5 mg/m³ groups. In these groups, increased liver, lung and thymus weights (males only) were reported. Irreversible pneumonitis (severity reduced at the end of the recovery period) and bronchitis were seen in the lungs of animals treated with 2.5 mg/m³ polihexanide.

The results from a 21-day repeat dose inhalation study conducted in rats (predates establishment of test guidelines) support the observations of the critical study above.

Genotoxicity

Based on the limited available in vitro and in vivo genotoxicity studies, polihexanide is not considered to be genotoxic.

Carcinogenicity

Based on several studies conducted in accordance with, or comparable to, United States Environmental Protection Agency, and The Organisation for Economic Cooperation and Development test guidelines, polihexanide induced vascular tumours in rats and mice at high doses only. The doses were above the maximum tolerated dose. As such, the effects may not be relevant under the conditions of human exposure.

Reproduction and developmental toxicity

Based on the available data from several animal studies, polihexanide is not expected to exhibit reproductive or developmental toxicity.

Observation in humans

Polihexanide, at concentrations up to 1.5%, was not irritating to the skin in a skin irritation study in human volunteers. In clinical case reports, 0.02% of aqueous polihexanide solution used in the treatment of Acanthamoeba keratitis was tolerated by human corneal and conjunctival epithelium.

In an unpublished 2016 report, the Australian Government Department of Health conducted a detailed evaluation of the available skin sensitisation studies and concluded that polihexanide is a possible skin sensitiser in humans in product formulations at 0.5%, with a potential for causing sensitisation at 0.2% in sensitive individuals.

The following case studies have been reported:

• two cases of severe anaphylaxis were reported following contact with a surgical wound treated with hospital disinfectant containing 0.2% polihexanide;
• an 81-year old female patient experienced symptoms of a grade III anaphylaxis with palmar pruritus, flush, swelling of lips, swallowing difficulties, hypotension and loss of consciousness while using a new brand of wet toilet paper (brand name not provided) containing polihexanide as a disinfectant. The patient had no previously known allergies or atopic diseases. Based on the detailed allergy history, the patient had experienced episodes of grade II anaphylaxis during wound care of an existing leg ulcer: once when using a new wound dressing; and twice after wound cleansing with two different disinfectant products. According to the product data sheets (available online), the wound dressing and disinfectants contain the following polihexanide concentrations: 0.3%, 0.02% and 0.1%;
• six out of 1554 patients showed positive skin reactions following patch tests at a concentration of 2.5% polihexanide on individuals with known contact allergen responses to cosmetics and medications;
• no adverse effects were noted following the exposure of 29 patients to a product, a pre-operative antiseptic for cataract surgery containing 0.2% polihexanide; and
• a 2% concentration of polihexanide is capable of causing skin sensitisation which can be elicited from 0.2% from a human repeat insult patch test (HRIPT) of 191 human volunteers.

Public exposure

There are no cosmetic or domestic uses identified for polihexanide in Australia. However, overseas information indicates such uses are likely in Australia.

Pre-meeting public submissions

Three (3) public submissions were received for polihexanide. One (1) submission raised no objections as it outlined that the proposed scheduling amendment would not have any impact on therapeutic goods. One (1) submission was opposed and one (1) submission supported the proposal for cosmetic products, but opposed the proposal for non-cosmetic products.

Main points in support:

One submission also requested an amendment to the index entry and a longer implementation date:

• Reducing the cut-off concentration for polihexanide from 5% or less to 0.3% or less when used in cosmetics is in line with current EU requirements (SCCS Opinion 2017) for cosmetic use. It is also in line with expert, peer-reviewed assessments which conclude that polyaminopropyl biguanide (PHMB) is not safe at a maximum concentration of 0.3%.
• There are various synonyms for these 2 substances. For clarity, entries for the following names should be included in the index and cross-referenced to the polihexanide schedule entry: polyhexamethylene biguanide (PHMB), CAS number 28757-47-3 and polyhexamethylene biguanide (PHMB) hydrochloride, CAS number 27083-27-8.
• An adequate transition period would be required to allow for any labelling changes that may be required as these changes could affect products currently in the Australian market with an established history of safe use. There is no evidence that would suggest immediate action is required for the risk management of this substance.

Main points opposed:

• The suggested scheduling does not appear to be sufficient to provide a high level of consumer health safety and is inconsistent with current international, expert peer reviewed assessments.
  • The current and sustained presence of polihexanide in the Australian market place has not been properly identified. It is widely used in leave on applications including on sensitive facial skin and newborn and infants.
  • Inappropriate assumptions were made when considering the relevance of the 2014 SCCS report that concluded "On the basis of the data available, the SCCS concludes that Polyaminopropyl Biguandide (PHMB) is not safe for consumers when used as a preservative in all cosmetic products up to the maximum concentration of 0.3%."
  • Polihexanide is suspected of causing cancer (Carc 2 H351).
  • The 2017 SCCS is of the opinion that the use of polihexanide as a preservative in all cosmetics up to 0.1% is safe. A more appropriate scheduling for leave on cosmetic use is Schedule 6 with a 0.1% concentration limit. For rinse off cosmetic use, a Schedule 5 entry with a 0.1% concentration limit is more appropriate.
• There is no new information since the 2015 scheduling consideration of this substance that would indicate changes to the 5% concentration in non-cosmetic products are necessary.
• According to the 2017 EU SCCS opinion "with respect to potential contribution of exposure from non-cosmetic use to the overall exposure… it is considered that the actual future consumer related exposure to PHMB is considered in practical terms to be very low."

The public submissions will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegates

The committee recommended that the current Schedule 6, Appendix F and Index entries for polihexanide be amended, as follows:

The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

1. the risks and benefits of the use of a substance:

• The benefit of polihexanide is that it is an effective preservative.
• The risk of polihexanide is that it is a skin sensitiser at higher concentrations.

• the purposes for which a substance is to be used and the extent of use of a substance:

• Polihexanide is in use in cosmetics and therapeutic goods

• the toxicity of a substance:

• Polihexanide is highly irritating to eyes in rabbit studies and a moderate skin sensitiser in animals; high acute and repeated inhalation toxicity in animals.
• Polihexanide is a known skin sensitiser in humans.

• the dosage, formulation, labelling, packaging and presentation of a substance:

• 0.3% of polihexanide aligns with international regulations.

• the potential for abuse of a substance:

• Nil.

• any other matters that the Secretary considers necessary to protect public health

• Nil.

Delegate's considerations

The delegate considered the following in regards to this proposal:

• Scheduling proposal
• ACMS advice
• Public submissions received
• Section 52E of the Therapeutic Goods Act 1989
• Scheduling Policy Framework (SPF 2015)

Delegate's interim decision

The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

1. the risks and benefits of the use of a substance:

• The benefit of polihexanide is that it is an effective preservative.
• The risk of polihexanide is that it is a skin sensitiser at higher concentrations.

• the purposes for which a substance is to be used and the extent of use of a substance:

• Polihexanide is in use in cosmetics and therapeutic goods

• the toxicity of a substance:

• Polihexanide is highly irritating to eyes in rabbit studies and a moderate skin sensitiser in animals; high acute and repeated inhalation toxicity in animals.
• Polihexanide is a known skin sensitiser in humans.

• the dosage, formulation, labelling, packaging and presentation of a substance:

• 0.3% of polihexanide aligns with international regulations.

• the potential for abuse of a substance:

• Nil.

• any other matters that the Secretary considers necessary to protect public health

• Nil.

---